Effectiveness of lenalidomide in relapsed primary cutaneous diffuse large B‐cell lymphoma, leg type

Key Clinical Message The primary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL‐LT) has a poor prognosis. R‐CHOP with or without radiotherapy is the available recommendations for first‐line treatment. Relapses/refractory cases are frequent with no standardized therapeutic guidelines. Lenalidomide seems to be an excellent therapeutic option as a second‐line treatment of relapsed PCDLBCL‐LT.

CT scan showed complete control of PCDLBCL-LT on June 2010 with clearance of the cutaneous and mediastinal lesions. However, the patient developed neutropenia, and the sixth cycle was not performed.
The patient then developed a relapse of both cutaneous and mediastinal lesions in September 2010 ( Figure 1B). The second course of R-CHOP did not control the disease and was responsible for hematological toxicity, including severe neutropenia. Lenalidomide (10 mg/day for 21 days of every 28-day cycle) was proposed on November 2010, associated with a dexamethasone 20 mg on days 1-7-14 monthly.
This treatment was well tolerated and permitted a good control with a complete disappearance of the cutaneous nodules with control of 5 months of her lymphoma. The lymphoma then progressed by the 6th month (on May 2011) with a rapid progression of the mediastinal mass. She deceased on June 2011.

| DISCUSSION
PCDLBCL-LT is rare non-Hodgkin's lymphoma (2.6% of primary cutaneous non-Hodgkin's lymphomas), affecting elderly people (median age of 76 years), 1 and known by its aggressive behavior and poor prognosis. It is represented by solitary or multiple rapidly growing nodule localized mainly on lower limb unilaterally or bilaterally. Ulceration of these lesions is possible. [2][3][4] Unlike other primary cutaneous B-cell lymphomas, secondary extracutaneous dissemination is common, 3,4 including lymph nodes, central nervous system, bone, and liver. 1,8 PCDLBCL-LT is characterized by the positivity of MUM-1, CD20, and high Bcl-2 expression with lack of CD10. 2,9 Dual expression of both bcl-2 and c-myc is also common and associated with inferior overall survival. 3,10 However, up to 10% of PCDLBCL-LT presents lack of bcl-2 and Mum-1 staining. 1 Genetically, NF-κB pathway-activating mutations were observed in PCDLBCL-LT, and this includes CD79B, CARD11, and the mutation of MYD88 which was confirmed to be the most prevalent mutation (~75%). 3,9,11 Moreover, MYD88 mutation can be used as a diagnostic feature to differentiate PCDLBCL-LT from the primary cutaneous follicular large B-cell lymphoma. 9 The main adverse prognostic factors include multiple lesions, old age, MYD88 mutation, advanced T stage of the tumor, and leg localization of the lesion. 2,4,5 First-line treatment in the diffuse or multifocal form of PCDLBCL-LT is as in diffuse large B-cell lymphomas (DLBCL) 3 depends on polychemotherapy associating rituximab (R-CHOP) with or without radiotherapy. 12,13 This combined therapy could be replaced by less-aggressive treatment of rituximab and polychemotherapy (R-PCT) in oldest or frailest patients. 2,4 However, for the solitary lesion, radiotherapy should be considered as a first-therapeutic choice. It could also be treated by surgical resection. 8,12,13 Additionally, it has been observed that the 5-year survival rate has been increased by about 65% to 75% over time since the use of rituximab-PCT with or without anthracyclines. 2 Nevertheless, neutropenia and consecutive infection are the main adverse effect and cause of morbidity and mortality in this treatment. 2 Spontaneous remission of PCDLBCL-LT is extremely rare, and it was reported in five cases. 1,14,15 The cause of this spontaneous regression in unknown, and it has been described as a result of probable response of immune system to bacterial or viral infection, or traumatic causes including biopsies, or apoptosis or particular condition of the tumor microenvironment as well. 1,14,17 All biopsies taken after regression of the published cases showed superficial and deep dermal inflammatory T-cell infiltrate suggesting that un inadequate T-cell immune response may play a role in the disease pathogenesis.
Refractory cases to R-PCT are possible, and rapid recurrence after initial treatment is still frequent and remains a challenging issue due to lack of standardized therapeutic protocol. 2,4,7 Lenalidomide (Revlimid®) is a derivative of thalidomide, 18 and it is an oral immunomodulatory agent with multiple mechanisms of action that interfere with the growth of aggressive non-Hodgkin's lymphomas through alteration of the tumor microenvironment and enhancing the cytotoxic activity of T cells and natural killer cells. 19 It performs an inhibition of cell signaling engaging NF-κB and IFN-β, through its antiproliferative and antiangiogenic effects. 4 Lenalidomide was approved in December 2005 by the FDA for the treatment of red blood cell transfusion-dependent anemia due to myelodysplastic syndrome (MDS) associated with a chromosome 5q31 deletion. It is also indicated in the treatment of other conditions, including plasma cell malignancy, mantel cell lymphoma, cutaneous T-cell lymphoma, and multiple myeloma. 20 The most common adverse events are neutropenia and thrombocytopenia. 19 The efficacy of lenalidomide was demonstrated on relapsing and refractory DLBCL, and it looks to be a good candidate for PCDLBCL-LT. 4 Thus its effectiveness was discussed previously in two case reports of relapsed PCDLBCL-LT, showing partial remission of the disease with excellent tolerance of the treatment in an 83-yearold woman. 6 And the complete resolution was obtained after combined therapy of lenalidomide with rituximab in a 78-year-old woman. 7 The efficacy of single-agent lenalidomide in relapsed/refractory PCDLBCL-LT was recently discussed in a small phase II study (n = 19), and the 6-month overall response rate was 26%. However, the response was significantly higher with the absence of the MYD88 mutation. 4 This observation underlines the interest of the association lenalidomide-dexamethasone in the management of PCDLBCLs-LT.

| CONCLUSION
PCDLBCL-LT has a poor prognosis with no standardized treatment recommendations available in relapsed forms. The adverse therapeutic effects are most likely related to the advanced age and poor general condition of patients. A combined lenalidomide therapy, as well as more targeting monotherapy, deserves to be evaluated as a second-line treatment for this affection.